Portable equipment for administration of fluids into tissues and tumors by convection enhanced delivery technique

ABSTRACT

The present invention is directed to a device for a portable convection enhanced delivery system that allows administering liquids to specific locations within the body, especially tissues and tumors also allowing outsubject treatment. The application system comprises a portable extracorporal pump with a fluid reservoir that is connected via an infusion system to an infusion catheter placeable to any tissue or tumor the fluid should be administered to by high flow microperfusion. The system enables administration of fluids of any kind by convection enhanced delivery also in out-patient treatment. The system can be used for delivering various drugs, proteins, protein toxins, antibodies for treatment or imaging, proteins in enzyme replacement therapy, growth factors and viruses or oligonucleotides in gene therapy etc. The application methods as well as the surgical method to implant this device are enclosed to this invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/420,094, filed Apr. 22, 2003.

FIELD OF THE INVENTION

The present invention relates generally to systems, kits, and methods ofuse for a medical device implantable in a subject's body. The systemrelates to a device for a convection enhanced delivery system, oftenregarded as high pressure microperfusion, comprising at least one pumpwith a fluid reservoir, an infusing system and an infusion catheter. Theinfusing system comprises at least a tube connecting the outlet of thepump with the infusion catheter. The methods for delivering drugs to asubject and implanting the device are also disclosed.

BACKGROUND OF THE INVENTION

A major hurdle in the development of many pharmaceutically active drugsis to find an appropriate delivery form for their administration in asubject to achieve a therapeutic level at the site of action.Additionally, if the target of the drug is a specific organ or alocalized tumor, systemic administration may not be sufficient to reacheffective drug concentrations at the target site to achieve the desiredtherapeutic effect. For example, many oligonucleotides or proteins,often of large molecular weights (for example, antibodies, hormonesetc.), are found to be efficient drugs in vitro, but it is oftenproblematic to reach an effective concentration of the drug at their invivo target to illicit a therapeutic effect.

Another hurdle to overcome in administering drugs to a subject iscrossing the blood-brain barrier. The blood brain barrier is very oftenan impenetrable obstacle for substances to cross even when thesubstances are administered intravenously. Difficulties in penetratingthe blood-brain barrier can be traced to many causes, including, forexample, a particular drug's chemical stability characteristics, itsmolecular weight, and/or its chemical charge and polarity etc.

Other drugs have toxic effects and therefore should only be administeredlocally. In the same context, imaging substances for example may best besuited for local administration to minimize systemic toxic side effectsand/or improve their performance.

Existing techniques for regional drug delivery, such as impregnatedpolymer discs or bolus injections, depend on physical diffusion todistribute the agent. Often the distribution of large molecules isrestricted and the rate of distribution is inversely related to the sizeof the agent and is slow relatively to tissue clearance. But even drugswith ideal characteristics for diffusion very often attain littlesatisfactory concentrations in the margins of the tissue or the tumor.In the case of lethal tumors, cell populations that exist beyond thesite of drug delivery escape exposure to the drug because ofinhomogeneous infusion determined to the concentration gradient thatdevelops between the site of injection and the advancing tumor border.

For convection enhanced delivery of drugs into brain tissue a highlysophisticated delivery system has been described, see for example, PCTpublication WO 95/05864. Substances are administered with a specificflow into a tissue or a tumor (for example, 0.5 to 15.0 μL/min) and theconcentration of the drug spreads homogeneously around the infusionsite. This convection enhanced delivery technique has only been possiblewith huge and heavy syringe pumps since the demand towards thecontinuity of flow characteristics is very high. The syringe pumps aredescribed as being connected directly with the catheter which ispositioned into the brain. Portable pumps used for the application ofdrugs into the vein, the interstitium or intraspinal applications havebeen regarded to have insufficient flow characteristics for this use.Also, a catheter directly accessing the target tissue can be used onlyduring clinical treatment, but has to be renewed after some time (hoursor days, for example) because the entrance has the potential to becomeinfected.

The necessity for huge, non-portable syringe pumps and its directcombination with the catheter for implantation into the brain hasrestricted the use of this application system to in-patient treatmentonly. In particular, it is very inconvenient for the subject when thecatheter is exposed or visible outside the body (for example, the head)during out-patient treatment. Beside this cosmetic disadvantage for thesubject, the exposed catheter brings an additional risk of infection asthe site of entry can be easily manipulated by mechanic strain.Furthermore, repeated surgery for implantation of a new catheter isdesired in interval therapy. These surgeries are additionalpsychological obstacles as well, and involve a high risk of anadditional infection and further complications for the subject.

The administration of drugs especially to the brain by indwelling pumpshas also been describe in context with the treatment of movementdisorders, see for example, U.S. Pat. No. 5,711,316, or withneurodegenerative disorders, see for example, U.S. Pat. No. 5,735,814.Whereas the technique of these apparatus is highly sophisticated,comprising a sensor as well, it would not fit the demands of convectionenhanced delivery administration into a brain tumor. For example, thesepumps have insufficient flow characteristics to be used in thisapplication. Additionally, in the administration of fluids over a longperiod of time (for example, days, weeks or months) the electric supplyof the pump will likely require recharging or replacement leading tofurther surgical intervention. Furthermore, for interval treatment incombination with huge volumes of solvents the supply of these solventshas to be extra-corporal or else otherwise additional surgeries would benecessary.

The administration of substances periodically via a access port systemthat can be connected with a catheter has also been described, see forexample, U.S. Pat. No. 5,897,528. Access ports are in general chamberscovered with a septum, which enables repeated puncture with a needle.The access port is connected via a access port catheter and a connectorwith an infusion catheter. This system allows repeated administration ofpharmaceutical fluids. The positioning of the catheter during periodicadministration of drugs as so far described, is restricted to bodyfluids (for example, interstitial fluids) because by implanting thecatheter into a tumor or tissue, the openings of the catheter becomeovergrown with cells, especially tumor cells, when located herein andclosed thereby during the time no solvent is administered.

Therefore, there remains a need for the administration of a therapeuticagent to a subject with continuous flow by employing convection enhanceddelivery technique during out-patient treatment that is suitable forinterval therapy, minimizes the number of surgeries needed forimplantation and maintenance, is convenient to handle and/or iscomfortable to wear during use. A faster onset of action, improvedside-effect profile, enhanced stability, reduced dosing amount andfrequency, and improved patient compliance are also desired for thedelivery of therapeutic agents to a subject. In addition, it would bemuch desired to have a system having an indwelling pump and a catheterthat can be located intrathecally. The discussion that follows disclosesdelivery systems, kits, and methods that help to fulfill these needs.

SUMMARY OF THE INVENTION

The effective administration of a fluid pharmaceutical agent to aspecific location within a subject is complicated by the complexities ofan in vivo system and the agent's physical and chemical properties. Adevice has been discovered that effectively delivers atherapeutically-effective amount of a liquid pharmaceutical agent to asubject that allows administration of the agent to a specific locationwithin a subject, for example, a particular tissue or tumor. In oneembodiment of the present invention, a portable convection enhanceddelivery system administers a pharmaceutical agent in a liquid form to aspecific location within a subject. In yet another embodiment of thepresent invention, the system comprises a portable extracorporal pumpwith a fluid reservoir that is connected via an infusion system to aninfusion catheter implantable in a tissue or tumor of a subject. Thefluid in one embodiment of the present invention, is administered byhigh flow microperfusion. The system can be used for delivering varioustherapeutic agents, such as, for example, drugs, proteins, proteintoxins, imaging agents, antibodies for treatment or imaging, proteins inenzyme replacement therapy, growth factors, and/or viruses oroligonucleotides in gene therapy, etc. These delivery systems have beenfound to improve bioavailability and safety, as well as improve thepharmacokinetic and pharmacodynamic properties of the deliveredtherapeutic agent. The present invention also enables for the first timeout-patient treatment with convection enhanced delivery technique usinga portable pump. The present invention comprises these delivery systems,kits based thereon, and methods for the preparation and use thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Other advantages of the present invention will be readily appreciated asthe same becomes better understood by reference to the followingdetailed description when considered in connection with the accompanyingdrawing wherein:

FIG. 1 shows an apparatus comprising a portable pump (2) with a solventreservoir (1), an infusion tube (3) with a filter (4), an access system(5) (access port needle), connecting the infusion tube with an accessport (6), an access port catheter (7) connected with a connector (8)with one infusion catheter (9), which is positioned with its perfusionholes into the target (10), tissue or tumor. The device left hand of thebroken line is extracorporal, and right hand of the broken line areindwelling.

FIGS. 2 a and b depict the flow characteristics of a syringe pump(“Graseby® 3200”, Fa. AxMediTec) often used in clinics for convectionenhanced delivery application. FIG. 2 a depicts the flow characteristicat a set flow of 240 μL/h FIG. 2 b shows the flow characteristic of thatpump at a set flow of 480 μL/h.

FIGS. 3 a and 3 b depict the flow characteristic of a Portable Pump(“Pegasus Vario” from the company LogoMed). FIG. 3 a depicts the flowcharacteristic at a set flow of 240 μL/h. FIG. 3 b shows the flowcharacteristic at a set flow of 480 μL/h.

FIGS. 4 a and 4 b depict the distribution of Evans blue dye in anisotropic 0.4% agarose gel which is proved to be an appropriate model tosimulate brain diffusion characteristic. Images were taken at 0, 1, 3,6, 12 and 24 hours of infusion time. FIG. 4 a depicts the distributionof the radial piston pump “Pegasus Vario” at a flow of 480 μL/h, whereasFIG. 4 b depicts the distribution of the high sophisticated syringe pump“Graseby® 3200” so far used for convection enhanced delivery techniqueat a flow of 480 μL/h.

FIGS. 5 a and 5 b depict an access system, comprising an access portneedle (5 a) bent with an angle of 90°, and a transparent cap (5 b),that is lined by a ring of soft material (5 c). FIG. 5 a depicts thesectional view, FIG. 5 b depicts the view from below.

FIG. 6 depicts the sectional view of an access port with one chamberwith the casing (6 a), a septum at the distal end (6 b) and an outlet atthe proximal end (6 c).

FIG. 7 depicts schematic side view of an infusion catheter (9) with itstip at the proximal end (9 a), the entrance at the distal end (9 c) sideand a region (9 b) where the perfusion holes are arranged.

FIG. 8 depicts a sectional view of an access port with two port chamberswith the casing (6 a), two septa at the distal end of each chamber (6 b)and two outlets (6 c), one for each chamber, and a needle screencovering one of the chambers (6 d).

DETAILED DESCRIPTION OF THE INVENTION

Referring to the drawings, the application system according to thisinvention enables the administration of substances dispersed ordissolved in, for example, an aqueous media, even in large volumes,during several hours, days, weeks, months, or years of treatment to atissue or tumor by convection enhanced delivery technique.

Initially referring to FIG. 1, one embodiment of an apparatus of thepresent invention is shown. This particular embodiment comprises aportable pump (2) with a solvent reservoir (1), an infusion tube (3)with a filter (4), an access system (5) (access port needle), connectingthe infusion tube with an access port (6), an access port catheter (7)connected with a connector (8) with one infusion catheter (9), which ispositioned with its perfusion holes into the target (10), tissue ortumor. The portions of the device on the left hand of the broken lineare extracorporal, and on the right hand side of the broken line areindwelling.

Referring to FIGS. 5 a and 5 b, one embodiment of an access system isshown that comprises an access port needle (5 a) bent at an angle of90°, and a transparent cap (5 b), that is lined by a ring of softmaterial (5 c). The scope of the top as well as the angle may differfrom that shown. FIG. 5 a depicts the sectional view, FIG. 5 b depictsthe view from below.

Referring to FIG. 6, a sectional view of one embodiment of an accessport is shown comprising one chamber with the casing (6 a), a septum atthe distal end (6 b), and an outlet at the proximal end (6 c).

Referring to FIG. 7, a schematic side view of one embodiment of aninfusion catheter (9) is shown with its tip at the proximal end (9 a),the entrance at the distal end (9 c) side and a region (9 b) where theperfusion holes are arranged.

Referring to FIG. 8, a sectional view of one embodiment of an accessport is shown containing two port chambers with the casing (6 a), twosepta at the distal end of each chamber (6 b), and two outlets (6 c),one for each chamber, and a needle screen covering one of the chambers(6 d).

The portability of the pump-system allows infiltrating the target (forexample, a tissue or a tumor) with a soluble or suspended drug withoutlimitation to in-subject treatment.

In one embodiment, the application system is configured for out-patientapplication.

The portable application system further enables rinsing the implantedcatheter with a physiological fluid to prohibit its clogging by cellulargrowth during the time when no drugs are administered. Thus, intervaltherapies, without repeated surgery for implanting a new infusioncatheter, becomes possible.

In addition, the pump in combination with a access port system opens aneasy procedure to remove the pump for supplementary procedures such asmaintaining or exchanging the pump and/or the infiltration tube,recharging the batteries, refilling the reservoir and/or changing theinfiltration fluid, which can be useful for long term and intervaladministration and which has not typically been possible withoutadditional surgery by an implanted pump.

The convection enhanced delivery application systems according to thestate of art comprise only an infusion catheter and a heavy non-portablesyringe pump. In one embodiment of the present invention, the apparatusutilizes a light weight portable pump and an additional access portsystem. In yet another embodiment of the present invention, the infusioncatheter, the connector and the access port system are completelyindwelling. In another embodiment of the present invention, the infusioncatheter, the connector and the access port system with the access portcatheter are completely indwelling. The entrance into the body isreduced to a small needle that is covered by a transparent cap with asoft lining in one embodiment. This device reduces the danger ofcontamination and infections coming from the puncture site. In case ofchanging components of the apparatus, for example, the fluid reservoir,the access port needle can be exchanged by a sterile one.

Using an access port system in combination with an infusion catheter forthe administration of a substance dispersed or dissolved in fluids intotumors or tissues opens the widespread advantages of access port systemsalso for the field of, for example, convection enhanced deliveryapplication where access port systems have not used to date. In oneembodiment of the present invention, the infusion catheter is in fluidcommunication with an access port catheter and an access port issurgically implanted such that both of these can be completelyindwelling. Thus the entrance into the body is reduced to the accessport site. In one embodiment the access to the access port is a smallaccess port needle covered by a transparent cap with a soft lining.

Furthermore the access port system can be positioned at any appropriatelocation favourable to the position of the portable pump, and/or to theconvenience of the subject, and/or to the mechanic stability of theaccess port system (for example, over a rip).

The use of an access port system in combination with an infiltrationcatheter allows for exact placement of the infusion catheter in a onestep surgical procedure into the center of a tissue or tumor. In anotherstep, the access port system can be positioned in appropriate manner(for example, over a rip) and the access port catheter then can be laidslackly toward the entrance of the infusion catheter. In another stepthe two implanted catheters can be substantially permanently connectedwith an appropriate connector. This not only allows additional surgicalprocedures, but can also take into account the influence of mechanicstress at the position of the infusion catheter. The position of theinfusion catheter can be located to minimize such mechanical stress.

The present invention of using a access port system in combination withan infusion catheter for the administration of substances dispersed ordissolved in fluids into rapidly growing tumors or tissues opens thewidespread advantages of access port systems for the field of, forexample, convection enhanced delivery application, which has notpreviously been described in the art.

In contrast thereto, diffusion using a pressure gradient-dependentconvection-enhanced delivery of therapeutic agents has shown to producea bulk flow current that has the potential to homogeneously distributeeven large molecules through much greater distances throughout thetissue or tumor.

The applicant has surprisingly found that portable pumps, so far notaccepted to be usable for convection enhanced delivery techniquesbecause of their discontinuous flow characteristics, can be applied forconvection enhanced delivery technique in combination with at least oneinfiltration catheter of the present invention. The portable pumpenables for the first time out-patient treatment with convectionenhanced delivery technique. Further using a access port systemcomprising a access port chamber with a access port catheter and aninfusing tube with a access port needle, the advances of access portsystem technology additionally are accessible with the device forconvection enhanced delivery administration.

Before the present invention, clinically useful constant flows ratesused in conjunction with convection enhanced delivery could only beachieved with syringe pumps, such as, for example, a Graseby® 3200 or aHarvard® 2100. These syringe pumps are typically connected directly toan infusion catheter or connected by an infusion tube implanted into atissue such as brain tissue, as described in the internationalpublication WO 95/05864. The maximal oscillation of these syringe pumpswhen used in combination with an infusing tube, an access port, anaccess port catheter and a filter was as low as about 0.05 mL/h and aoscillation with a frequency of about 0.7 sec⁻¹ at a set flow rate of0.48 mL/h as shown in FIG. 2 b.

The flow characteristic of various portable pumps delivered in steps ofabout 0.05 mL to about 0.1 mL even in continuous flow mode, thusproviding high oscillations of the actual flow. This high oscillationvalue is not optimal for use with convection enhanced delivery in manytissues, particularly, for example, into brain tissue where constantflow rates of 0.1 μL/min to 15.0 μL/min are desired. One device claimingto deliver at minimal steps of 0.4 μL in the continuous flow mode wastested by the applicants. Since it is known that tubing and otherdevices may smoothen the flow characteristic applicants connected aninfusion tubing, an access port with an access port catheter and afurther infiltration catheter to the pump and recorded the flowcharacteristic. Despite of the smoothing influence of the device theportable pumps showed a flow characteristic with a 20 fold higheroscillation than those shown by comparator syringe pumps (FIGS. 2 a and2 b) in the same test setting.

The flow characteristics of the portable pump under test (“PegasusVario, Fa. Logomed) at a set flow of 480 μL/h showing an oscillation ofup to 1 mL/h with a frequency of 0.3 sec⁻¹ is depicted in FIG. 3 b. Theflow characteristics were recorded using a specific “liquid flow”measurement system at Institut für Mikro- and Informationstechnik,Villingen Schwenningen, Germany. The measurement compares the flow ofthe tested system with a reference flow using calibrated sensors of thecompany Bronkhorst applying hydrostatic technique (SP45, type:300×600tp45). Details of the experiment are described in Example 3.

Surprisingly, applicants found that this rough flow characteristic ofthe portable pump (Pegasus Vario, Fa. Logomed) was still suitable forthe convection enhanced delivery when used in conjunction with thepresent invention. The completed experiment carried out to demonstratethe suitability for convection enhanced delivery technique of the pumpshowing the flow characteristic is described in Example 1.

In one embodiment of the present invention, the device induces a flowcontinuously higher than about 0.001 mL/h and in average lower thanabout 0.5 mL/h is appropriate for convection enhanced delivery in braintissue if the total flow volume within one period of the oscillation isless than about 0.5 μL and the amplitude of the oscillation is betweenabout 0.1 mL/h and about 0.8 mL/h.

Also desired for patient compliance is the cosmetic advantages of aninfusing system in a case where the target for the administeredsubstance is beyond a visible part of the body (for example, braintissue) where according to the state of art in convection enhanceddelivery application systems, the infusion catheter was hanging from thehead of the subject at the point of insertion.

Rinsing the perfusion holes of a catheter implanted into a tissue ortumor with a constant flow, as well as a periodical flow, prevents theperfusion holes of the infusion from overgrowth with cells, especiallyfrom, for example, quickly growing tumor cells, when the infusioncatheter is placed in tumor or tissue. Overgrowth is believed to happenrapidly as soon as no solvent is administered over a period of severalhours to days resulting in a blockage of the device. Thus administrationof substances directly into tissue (apart from body fluids or cavities)at repeated cycles with treatment-free intervals as well as during longterm administration become possible with the device according to thepresent invention. Additional surgeries for implanting the infusioncatheter connected with the danger of contamination and the resultinginfections necessary according to the state of the art thus are avoidedas well. The flows necessary to keep the perfusion holes open depends onseveral factors including, for example, the number of perfusion holes,their diameter and the rapidity of tumor cell growth. In one embodiment,the flow to prevent such overgrowth varies between about 0.001 mL/h toabout 1 mL/h final flow in the infusion catheter.

The fluid pharmaceutical agent suitable for use in the present inventioninclude any agent suitable for delivery in a solvent system, or, forexample, formulated for delivery in an aqueous solution, such as forsubcutaneous injection. Such pharmaceutical agents include, for example,analgetics, agents for the treatment of wounds, analeptics,anaesthetics, anthelmintics, anticoagulatives, antirheumatics,antiallergics, antiarrhythmics, antibiotics, antidementiva,antidiabetica, antidotes, antiepileptics, antihemorrhagics,antihypertonics, antihypnotics, anti migrain preparation, antimycotics,antineoplasics, anti-parcinson agent, antiphlogistics, antisenseoligonucleotides, antituberculosis drugs, anti-arteriosclerotic agents,biologic materials, blood flow stimulants, cholagogas, corticoids,cytokines, cytostatics, diagnostics, fibrinolytics, geriatrics,gonadotropins, hepatics, hormones and their inhibitors, hypnotics,immunglobulines, immunomudulators, immunotherapeutics, organ perfusionsolvents, proteins, protein toxins, protectives, sedatives, cardiacremedys, depressants and stimulants, minerals, muscle relaxants,neurotropic agents, oligonucleotides, ophthalmics, osteoporotic agents,otologics, psychopharmaceuticals, sera, thyroid preparations, vaccines,spasmolytics, urologics, vitamins, drugs, proteins, protein toxins,antibodies for treatment, proteins in enzyme replacement therapy, growthfactors, vectors, viruses in gene therapy and/or agents for diagnosis asagents or antibodies for imaging, x-ray contrasting mediums,oligonucleotides inhibiting the expression of, for example, TGF-β, MIA,c-erbB-2/HER-2, or IL-10, and/or combinations thereof. The activesubstances may be dissolved or suspended in a physiological solvent orin any other appropriate solvent. The above agents may in the form of afree base, or a salt, hydrate, ester, amide, enantiomer, isomer,tautomer, polymorph, prodrug, or derivative of these compounds. (Basedin part upon the list provided in The Merck Index, Merck & Co. Rahway,N.J. (2001)). The above mentioned agents as well as combinations thereofcan be used in the apparatuses, methods, kits, combinations, andcompositions herein described.

In one embodiment of the present invention, the surface of the apparatusin contact with the therapeutic agent may be coated in appropriatemanner. Illustratively, the coating can be an antiinfective, anantiviral, a fungicide, or a X-ray absorbing material. Furthermore thesurface can be modified by surface modifying groups in a way that bloodcompatibility, abrasion resistance, coefficient of friction andresistance to degradation or molecular adhesion are reduced.

In one embodiment, the flexible tubes are connected by a pipe or tubewith an outer and an inner diameter, with the outer diameter having aslightly greater diameter than the inner diameter of the tube that isconnected by this pipe preventing the solvent of the tube from escaping.In yet another embodiment, the outer diameter of the pipe or tube has aradial deepening or heightening to improve the seat of the tube on thepipe or tube. Squeezing the tube from the exterior to the connectingpipe the seat of the tube can further improve the connection.

The components of a device of the present invention can be fabricatedfrom a range of materials including, for example, a metallic, apolymeric, and/or a composite material, including materials such astitanium, high grade steal, aluminium, alloys, polymeric foams,plastics, stainless steel and/or metal, and combinations, mixtures, andmodification thereof. Materials intended for implantation into a subjectcan be made of biocompatible materials, such as, for example, polymers,polymeric segments of polystyrene, polyolefins, polyamides, orpolyurethane, and metals. Selection of such materials depends on anumber of factors including the mechanical properties desired, and theporosity, surface properties, and toxicity of the material.Illustratively, a component of the present invention can be made oftitanium, an alloy, stainless steel, a ceramic, silicon, Teflon®,polypropylene, polyethylene, polystyrene, polyolefins, polyimide,polyamides, polyurethane, PET, PETG, PETE, PE, PTG, HDPE, PC, PVC,nylon, urethane, and/or a co-polymer, for example, and may be laminatedwith or otherwise include a layer of gold, silver and/or aluminum (tominimize permeability to gas and liquids) sputtered or otherwisedeposited or incorporated therein. Some commercially available productsuseful in fabricating the present invention include, for example,BioSpan® segmented polyurethaneurea, Bionate® polycarbonate urethane,Elasthane™, and Elasthane™ polyetherurethane, which can be used inchronically-implanted medical devices. Elasthane™ has a chemicalstructure and properties similar to Pellethane® 2363. Thermoplasticsilicone-urethane co-polymers such as PurSil™ silicone polyetherurethaneand CarboSil™ silicone polycarbonate urethane can also be used in thepresent invention.

In yet another embodiment, the connecting device is a screw connection.Illustratively, the thread on one port fits a nut on another port suchthat fluid communication is possible. In one embodiment, between the twoports there is a seal which is self-sealing to prevent solvent fromleaking. In yet another embodiment, the nut of one port contains alocking system. Illustratively, a locking system is an eye attached to anut and several eyes at the counterpart port that allows easily fixingthe screw connection by a wire, nail, screw, stitch, etc. In yet anotherembodiment, the connecting system is a bayonet joint comprising twocounterpart ports. The ports can be self-sealing. Bayonet joint includesintegrated locking systems. Many other technique according to the stateof the art can be applied in connecting ports of the present invention.

In one embodiment of the present invention, the apparatus contains adistributor, which in one embodiment can be a device containing a numberof proximal ports equivalent to the number of infusion catheters are tobe connected, a distal port, and a lumen therethrough. Illustratively,the distributor is indwelling and is made from a solid material, suchas, for example, a polymeric material, a plastic, and/or a metal. In oneembodiment, the distributor has appropriate connectors and lockingsystems for establishing permanent fluid communication with the accessport catheter and the infusion catheter. The diameter of the distal portand the accessory lumen in one embodiment, is large enough to supportall proximal ports with their accessory lumens with equivalent flow ofthe solvent. In one embodiment of the present invention, the equivalentdiameters of the proximal ports are less than the diameter of the distalport. In yet another embodiment, the diameters of the different proximalports differ from each other correlating to the type of infiltrationcatheter connected herewith (inner diameter of the infusion catheter,number of infusion holes, diameter of these holes etc.).

Within the low connection between the infusion catheter and the meansfor injection, a filter system may be integrated into the apparatus atany appropriate location. Illustratively, the filter system comprises asterile filter for removing pathogens; a biological filer for biologicalmaterials such as proteins and/or antibodies; a particle filter forremoving particulates; a chemical filter for removing chemicals; and/ora filter for removing air or gasses from the solvent. In one embodiment,each filter has a distal port and a proximal port and a lumentherethrough. Within the lumen of each filter there is a membrane or anyother appropriate device for removing air, particles, chemicals, and/orbiological materials, such as, for example, pathogens includingbacteria, fungi, and/or viruses. The different filter types are known tothose skilled in the art, and can have separate casings, or have commoncasings. In one embodiment, the filter for removing air is placed extracorporal. In yet another embodiment, the filter for removing particlesis positioned upstream the sterile filter. The sterile filter istypically characterised by a pore diameter of about 0.45 μm or less, orabout 0.22 μm or less, or about 0.1 μm or less. The particle filter ischaracterized having a pore diameter of greater than about 0.45 μm, orgreater than about 0.22 μm. In yet another embodiment, the filters areplaced in a sequence, from upstream to downstream, of air filter,particle filter and sterile filter. In yet another embodiment of thepresent invention, the filters are placed extra corporal, and have aflat profile that can be easily fixed on the skin. In yet anotherembodiment all filters are located outside the body, which facilitatesmaintenance and replacement. One or more filters of the same ordifferent category can be used in one embodiment of the device.

In one embodiment, the infusion catheter has an elongated body with aproximal port (see, for example, FIG. 7, 9 a), a distal port (see, forexample, FIG. 7, 9 c), and an interior lumen therethrough and perfusionholes. The lumen of the infusion catheter can be separated into severallumens.

In yet another embodiment of the present invention, the perfusion holesare in an area near to the proximal end of the infusion catheter.Illustratively, the infusion catheter material can be an inert material,a pliable material, and/or a biocompatible polymer, such as, forexample, a polymeric material, a plastic, and/or a metal, including,polypropylene, polyethylene, polyimide, polyamid, polyurethane, and/orsilicon.

In another embodiment of the present invention, the infusion cathetermay be stabilized with, or impregnated with a wire, to facilitate or actas a detectable marker that allows for monitoring the position of theinfusion catheter (for example, a barium compound in case of x-raymonitoring). The detectable marker can be restricted to the proximal endof the infusion catheter, and/or have scaling marks placed at regularintervals over the catheter.

Illustratively, the lumen of the catheter may be cylindrical, oval orangular and have one, two, three, or four or more lumens. The cathetercan have perfusion holes in any appropriate form, number, diameter andlocation depending on the tissue or tumor that is to be infiltrated. Theperfusion holes may be positioned for example, oppositely, radially,helically, symmetrically and/or asymmetrically around the axis of theinfusion catheter. The proximal end of the infusion catheter may besharp, obtuse, or round depending of the consistency of the tissue intowhich the infusion catheter is to be implanted.

In yet another embodiment of the present invention, the perfusion holecan come into existence by simply cutting off the proximal end of thecatheter. The catheter may be stabilized with a removable stylet made ofany appropriate material (for example, a polymeric material, a plastic,and/or a metal) stable enough to place the infusion catheter in thetissue or tumor and being removed after the catheter is at itsappropriate location within the tissue or tumor.

In another embodiment, the infusion catheter has an additional devicefor its fixation to a disc mesh, and/or a suture flange. In oneembodiment, the fixture has hole in the diameter of the catheter and oneor even more additional holes of appropriate diameter, that allows it toaffix the fixture with the catheter by a nail, screw, stitch, etc., to asolid tissue or bone. In yet another embodiment, the infusion catheterhas retention beads in any appropriate area.

For establishing fluid communication between corresponding ports of theembodiments described herein (for example, a reservoir, a pump, anaccess port, and/or infusion tube) a tube with two ports of any lengthand a proximal and a distal port can be integrated into the device. Thediameter of this tube has to be appropriate considering the flow, thevolume of the solvent that has to be injected. A tube might have alength to up about 1.5 m and a diameter from about 0.1 mm to about 5 mm.The material of the tube can be in one embodiment a flexible polymer.The infusion tube has a proximal port and a distal port and a lumentherethrough.

In one embodiment of the present invention, one or more of theindwelling parts and/or one or more of the parts that are in contactwith the fluid pharmaceutical agent and/or the physiological solutionare of materials that are physiologically compatible, and include, forexample, titanium, high grade steal, surface treated aluminium and theiralloys, ceramics, polymers such as polypropylene, polyurethane,polyethylene, polyimide, polyamide, silicon, Teflon®, and combinations,mixtures, and modification thereof.

In one embodiment of the present invention, the means for injecting asolvent has a proximal port and has a distal port or distal end and alumen therethrough. Means for injection comprises, for example,syringes, balloons, pumps or other device appropriate for infusing acertain amount of solvents once or several times with constant,increasing and/or decreasing flow as well as combinations thereof.

In one embodiment of the present invention, the one way valve has adistal port and a proximal port and a lumen therethrough. The one wayvalve comprises a device enabling the flow of a solvent only into onedirection. If the flow is in the other direction the valve is in aclosed position. The mechanism of the one way valve can be any mechanismknown to those skilled in the art, and can be based on, for example,spheres, membranes, lamellars, etc. The valves are integrated into theapparatuses at any appropriate place to provide the appropriatefunctionality desired. Illustratively, the one way valves comprisesconnecting and/or locking devices at their distal and proximal port.

In one embodiment of the present invention, the portable pump is a gaspressure pump, piston pump, radial piston pump, membrane pump, syringepump, centrifugal pump, suction pump, or any other mechanism inducing aflow characteristic according to the present invention. In yet anotherembodiment of the present invention, the flow characteristic of the pumpis enhanced by an expanding volume that is in fluid communication withthe lumen of the port downstream the pump mechanism. In one embodiment,the expanding volume is a soft tube with a closed distal end and an openproximal end and a lumen therethrough. This tube is in fluidcommunication with the solvent coming from the pump. The volume isexpanding during the time the pump feeds the solvent and the lumen iscontracting during the interval the pump feeds no solvent thus smoothingthe peaks of the flow.

In one embodiment of the present invention, the access port systemcomprises an accessory system, an access port casing and an access portcatheter. The access port chamber has a distal end and a proximal portand a lumen therethrough. The access port catheter as well has a distalend and a proximal end and a lumen therethrough. The access port chambercan be any commercially available access port system made of rigidbiocompatible material, including, for example, a metallic, a polymeric,and/or a composite material. In one embodiment the access port chamberhas appropriate devices for its fixation such as eyes for nails, suture,screws or hooks etc. Illustratively, the access port has one or morechambers.

In another embodiment of the present invention, the proximal port of theaccess port chamber is in fluid communication with the distal port ofthe access port catheter. As depicted in FIG. 6, the outlet of theaccess port chamber is a pipe (see FIG. 6, 6 c). In yet anotherembodiment, this pipe has at least one heightening or deepening thatimproves, in combination with an appropriate locking system, theconnection between the access port chamber and the access port catheter.

The access port catheter is from any pliable biocompatible material,including, for example, a metallic, a polymeric, and/or a compositematerials. The access port catheter can be stabilized with a wire or anycomparable technique for improving its implanting. The wire can beremovable. The catheter can be impregnated or contain a detectablemarker that allows to monitor the position of the catheter (for example,barium compounds in case of x-ray monitoring).

The access port casing and the access port catheter are implantedsubcutaneously. The accessory system is any device that enables fluidcommunication between the extracorporal infusion tube and/or means forinjection and the subcutaneously implanted access port chamber.

In one embodiment where using an access port needle as an accessorysystem the distal end of the access port chamber and is covered with aseptum made of resilient and pliable material such as silicon rubberthat is self sealing even if a needle is pricked through the septumseveral times. Any other technique for the accessory system allowing arepeated injection into the access port chamber may be used.

In yet another embodiment the access port system comprises two or moreof the above mentioned access port chambers. In one embodiment these twoaccess port chambers are integrated into one casing next to each otherand have the same structure as described for an access port system witha single access port chamber. One access port chamber is optionallycovered with a needle screen. In yet another embodiment the two accessport chambers are beyond each other. Both access port chambers can alsohave a septum. The proximal access port chamber has a smaller septumintegrated to the bottom of the distal chamber and additionally coveredwith a needle screen. Each access port chamber has its own proximal portin fluid communication with the distal port of the access port catheter.

In one embodiment of the present invention, the access port needle has adistal port and a proximal port and a lumen therethrough. The accessport needle in one embodiment is stable and long enough to connect theproximal port of the infusing tube with the distal end of the accessport chamber, after the access port chamber is implanted subcutaneously.In one embodiment the tip of the needle is bevelled to prevent thesilicon septum of the access port chamber from rupturing.Illustratively, the needle is straight or angled at between about 1° toabout 180°, or at about 1°, or about 15°, or about 30°, or about 45°, ofabout 60°, or about 90°, or about 120°, or about 150°, or about 180°. Inanother embodiment, the needle is covered with a transparent top, linedwith a soft, non-irritant material that prevents the surrounding of theinjection site from contamination.

The solvent reservoir is any device having a proximal port and a distalport or distal end and a lumen therethrough. In one embodiment of thepresent invention, the lumen is large enough to support the pump forseveral days at a flow rate leading to a final flow in the infusioncatheter of about 0.001 μL/h up to about 1 mL/h. In one embodiment thereservoir comprises two transparent cling films fit together at theirborder creating a receptacle with a flexible lumen. In one corner of thereceptacle a tube is integrated having a proximal port, a distal portand a lumen therethrough. The lumen of this tube is in fluidcommunication with the lumen of the receptacle.

In one embodiment of the present invention, the reservoir is integratedinto the casing of a portable pump. In yet another embodiment the sizeof the portable pump including the integrated reservoir is not largerthan about 125 cm³, 250 cm³, 500 cm³, 750 cm³, 1,000 cm³, 1,250 cm³,1,500 cm³, or 3,000 cm³. Illustratively, the reservoir is no larger thanabout 10 cm×15 cm×5 cm.

The materials and/or the construction respectively of all tubes, thereservoir, the catheters, access ports, filters and the pump can be suchthat the flow characteristic is not negatively influenced by movementsas described under definitions “Portable Pump” and usual operations withthe apparatuses.

All implanted devices, as well as devices in contact with the solventdetermined to be infused can be fabricated of material compatible withsterilization, including, for example, chemical, steam, and/or radiationsterilization, and can be sterile before use.

Illustratively, the apparatus of the present invention can be implantedinto a tumor where a solvent deliverable anti-tumor agent is indicated.Such tumors include, for example, a blastoma, breast cancer, esophagealcancer, head and neck cancer, ovarian cancer, sarcoma (including,osteosarcoma and chondrosarcoma), small-cell bronchogenic/lungcarcinoma, non-small-cell bronchogenic/lung carcinoma, colon carcinoma,colorectal carcinoma, gastric cancer, small intestine carcinoma, livercarcinoma, carcinoma of the kidney, pancreas carcinoma, gallbladdercancer, cervical carcinoma, endometrial cancer, mesothelioma, prostatecarcinoma, testicular carcinoma, brain tumor, non-Hodgkins lymphoma,Hodgkins-lymphoma, and/or a solid neoplasm.

The target tissue may include any tissue of the subject where treatmentwith a solvent deliverable therapeutic agent is indicated. Such tissuesinclude brain, bone marrow, bone, joints, thyroid, gall, heart, lung,muscle, spleen, kidney, liver, prostate, pancreas, stomach, vein andartery tissue.

Besides being useful in human treatment, the present invention is alsouseful for other subjects including veterinary animals, reptiles, birds,exotic animals and farm animals, including mammals, rodents, and thelike. Mammals include horses, dogs, pigs, cats, or primates (forexample, a monkey, a chimpanzee, or a lemur). Rodents includes rats,mice, squirrels, or guinea pigs.

One embodiment of an apparatus for delivering a solvent to a tissue or atumor according to the present invention comprises a means for injectinga solvent having a proximal port in fluid communication with a distalport of at least one infusion catheter, which is operatively implantedwith its proximal end into a tissue or tumor. In one embodiment, the twoports are fixed by a connecting and/or locking device.

In another embodiment, the apparatus may further comprise an infusingtube establishing fluid communication between the proximal port of themeans for infusing a solvent and the distal port of the infusioncatheter. In yet another embodiment, the device may additionally haveintegrated a filter system, one way valves inhibiting the proximaldistal reflux and/or additional tubes.

Yet another embodiment of an apparatus for delivering a solvent to atissue or a tumor according to this invention comprises two or moreinfusion catheters to improve the infiltration of the solvent into thetissue and/or tumor.

In one embodiment, the apparatus can further comprise a distributor witha number of proximal ports equivalent to the number of infusioncatheters, a distal port and a lumen therethrough.

The device of the present invention may additionally have an integratedfilter system, one way valves and/or additional tubes.

In yet another embodiment of apparatuses for delivering a solvent to atissue or a tumor according to this invention the means for injecting asolvent comprises a portable pump. The proximal port of the pump is influid communication with the distal port of at least one infusioncatheter. The distal port of the portable pump is in fluid communicationwith the proximal port of a solvent reservoir. In one embodiment, thedevice may further comprise an additional infusing tube establishing thefluid communication between the proximal port of the portable pump andthe distal port of the infusion catheter.

In yet another embodiment of the present invention, an apparatus fordelivering a solvent to a tissue or a tumor comprises a means forinjecting a solvent with the proximal port in fluid communication withthe distal port of an infusion tube. The proximal port of the infusiontube is in fluid communication with the distal portion of an access portchamber via an accessory system. The access port chamber issubcutaneously implanted, for example, over a rib. The proximal port ofthe access port chamber is in fluid communication with the distal portof the access port catheter and the proximal port of the access portcatheter is in fluid communication with the distal port of at least oneinfusion catheter. Several catheters might be in fluid communicationwith the proximal port of the access port catheter by an additionaldistributor. The proximal end of the infusion catheter is operativelyimplanted into the target tissue or tumor. In yet another embodiment ofthe present invention, the means for injecting a solvent and theinfusing tube are outside the body. All ports can be connected withappropriate connecting and locking device.

In one embodiment, the access port chamber, the access port catheterand/or the infusion catheter are indwelling.

In yet another embodiment, the pump with a reservoir and the infusingtube are outside the body.

Yet another embodiment of apparatuses for delivering a solvent to atissue or a tumor comprises a pump or a portable pump for injecting asolvent connected with its distal port to a reservoir or a syringe pumpbeing filled with an appropriate amount of solvent for infusing thetarget tissue or tumor for several minutes, hours, days or weeks. Theproximal port of the pump is in fluid communication with the distal portof an infusion tube. The proximal port of the infusion tube is in fluidcommunication with the distal part of an access port chamber by anaccessory system. The proximal port of the access port chamber is influid communication with the access port catheter and the proximal portof the access port catheter is in fluid communication with the distalport of at least one infusion catheter. Also several catheters might bein fluid communication with the proximal port of the access portcatheter by an additional distributor. The proximal end of the infusioncatheter is operatively implanted into the target tissue or tumor. Allports can be connected with appropriate connecting and locking device.

In yet another embodiment of the present invention, the apparatusesfurther comprises a ventricular shunt. The ventricular shunt cancomprise a tube of appropriate diameter that has a proximal endsurgically implanted into the intraspinal liquid and a distal port and alumen therethrough. The distal port of this shunt is in fluidcommunication with a body cavity, for example, a vein, anintraperitoneal space or a distal port of a access port system. In yetanother embodiment the ventricular shunt comprises at least one catheterwith its openings ending in the intraspinal fluid a distal port and alumen therethrough. This catheter can be elongated by further tubes aswell as one-way valves might be integrated. All parts can be connectedby appropriate connecting and/or locking device.

In yet another embodiment, the proximal port of the access port catheteris in fluid communication with the distal port of a distributor. Thedistal ports of two or more infusion catheters are in fluidcommunication with the equivalent number of proximal ports of thedistributor. In one embodiment, the ventricular shunt may additionallyhave one or more integrated one-way valves, an additional tube, and canbe connected by appropriate connecting and locking device.

In yet another embodiment of the present invention, the apparatuscomprises two access ports. The proximal port of one of the indwellingaccess ports is in fluid communication via the access port catheter andappropriate connectors and locking systems with the distal port of atleast one infusion catheter surgically implanted into a tumor or tissue.The distal port of this access port is in fluid communication with ameans for injection a fluid solvent. Further infusion tubes, filtersystems, accessory systems etc., may be integrated into this apparatusas described in the embodiments above. The proximal port of the secondaccess port chamber can be in fluid communication with the distal portof a second access port catheter. In one embodiment, the proximal portof the access port catheter is in fluid communication with theventricular shunt. In yet another embodiment, the distal end of thesecond access port chamber is covered by a septum allowing repeatedpricking with an access port needle and removing intraspinal liquid fordiagnostic and/or therapeutic reasons by means for removing a solvent.

The means for moving a solvent can be any device such as for example, asolvent reservoir, a syringe or a balloon. Additional tubes, valves orflow regulators can be integrated into the device. In one embodiment thedistal port of the access port needle is in fluid communication with atube having a distal port and a proximal port and a lumen therethrough.The distal port of the tube is in flow communication with the proximalport of a portable pump removing liquid from the intrathecal lumen. Theflow of removing intrathecal fluid in one embodiment is up to the flowthe fluid pharmaceutical agent or the physiological solvent isadministered into the tissue or tumor.

The diameters and length of all tubing, catheters connectors and portsof the apparatuses described in this application can have an appropriatescope corresponding to the flow rate.

Yet another embodiment of this invention comprises one of theembodiments described above wherein at least one of the lumens incontact with the solvent and/or the indwelling parts is sterile.

Yet another embodiment of this invention comprises any of theembodiments described above filled with a solvent that is selected fromthe physiological solvent and/or a fluid pharmaceutical agent.

Yet another embodiment of this invention is the use of one of theapparatuses described herein for administering the solvent to a targettissue or tumor applying convection enhanced delivery, which is alsonamed high pressure microperfusion. This generally means that thedelivery of a solvent induces a bulk flow current in the target tissueor tumor that has the potential to homogeneously distribute even largemolecules throughout a tissue or tumor. The flow of the solvent dependson the specific tissue or tumor the fluid pharmaceutical agent isadministered to and in some cases might be even higher than the rangesgiven here.

In inducing a bulk flow current in brain tissue, in one embodiment ofthe present invention, a continuous flow of a fluid pharmaceutical agentof about 0.001 mL/h up to about 1 mL/h is infused, or about 0.1 mL/h upto about 0.8 mL/h, or about 0.2 mL/h, or about 0.5 mL/h is infused.

In yet another embodiment of the present invention, the flow induced bya pump meets at least on of the following flow characteristics in atleast one of the infusion catheters: an average flow of between about0.001 mL/h or about 1.0 mL/h; a total flow volume within one period ofany oscillation of less than about 0.5 μl; and/or an amplitude of theoscillation between about 0.1 mL/h and about 1 mL/h.

In yet another embodiment of the present invention an apparatus thatinduces a flow in the infusion catheter as described herein appliesconstant average flows, increasing or decreasing flows as well ascombinations thereof.

In yet another embodiment of the present invention, the apparatus isused for interval therapy, meaning that the fluid pharmaceutical agentis administered alternating with another fluid pharmaceutical agentand/or a physiological solvent. The flow of the physiological solventduring the time no other fluid pharmaceutical agent is administereddepends on many factors including, for example, the target tissue.Illustratively, for convection enhanced delivery in brain tissue theflow can vary between about 0.001 mL/h to about 1 mL/h, or between about0.01 mL/h to about 0.4 mL/h, or between about 0.05 mL to about 0.3 mL/hin each infusion catheter. The pump in one embodiment also worksperiodically using increasing or decreasing flows, as well ascombinations thereof.

In yet another embodiment, the infusion catheter is surgically implantedwith its perfusion holes terminating in the tumor or tissue in which thefluid pharmaceutical agent is being administered to. The access portchamber connected with the access port catheter is implanted at anyappropriate location. In one embodiment, the access port catheter istunneled towards the open end of the infusion catheter. The access portcatheter as well as the infusion catheter can be shortened to anappropriate length, considering that they are laid slack enough tofollow movements of the body without influencing the exact position norof the infusion catheter neither of the access port. Finally the accessport catheter is connected with the infusion catheter by an appropriateconnector. In yet another embodiment, the implanted device is filledwith a physiological solution in which the fluid pharmaceutical agent isto be infused with.

Even if the description is focused on tumors and tissues, the method ofthis invention can be used for body cavities, veins and arteries aswell.

In yet another embodiment, the pump is portable and has a fluidreservoir large enough to support convection enhanced delivery forseveral days at a flow rate leading to a final flow in the infusioncatheter between 0.1 and 15 μL/min, or between 2 and 12 μL/min, orbetween 3 and 10 μL/min.

Up to now, to get a constant flow only syringe pumps such as thecommonly used “Graseby® 3200” syringe pump were clinically used forconvection enhanced delivery treatment for reasons of their constantflow characteristic. In one embodiment, the maximal oscillation of sucha syringe in combination with an infusing tube, a access port, a accessport catheter and a filter is as low as 0.1 mL/h within one secondaround the average flow rate of 480 μL/min as shown in FIG. 2 b.

In one embodiment, a pump showing a flow characteristic of anoscillation of 1 mL/h, or greater, within a second in combination with acatheter is appropriate for convection enhanced delivery technique.

In one embodiment of the present invention, the compounds administeredto the subject are formulated as an injectable formulation and comprise,for example, an aqueous solution or suspension of the compounds suitablefor intravenous delivery. When preparing the composition for injection,particularly for intravenous delivery, illustratively, the continuousphase comprises an aqueous solution of tonicity modifiers, buffered to apH below 7, for example, or below 6, for example. The tonicity modifierscomprise, for example, sodium chloride, glucose, mannitol, trehalose,glycerol, or other pharmaceutical agents that renders the osmoticpressure of the formulation isotonic with blood. Alternatively, when alarger quantity of the tonicity modifier is used in the formulation, itcan be diluted prior to injection with a pharmaceutically acceptablediluent to render the mixture isotonic with blood.

In another embodiment of the present invention, a preservative is addedto the formulation. Illustratively, a preservative includes benzalkoniumchloride, propylparabem, butylparaben, chlorobutanol, benzyl alcohol,phenol, sodium benzoate, or EDTA.

The compositions of the present invention can further comprise apharmaceutically acceptable carrier. The carrier materials that can beemployed in making the compositions of the present invention are any ofthose commonly used excipients in pharmaceutics and should be selectedon the basis of compatibility with the pharmaceutical agent and therelease profile properties of the desired dosage form. Illustratively, apharmaceutical excipient except active drugs are chosen below asexamples:

-   (a) Binders such as acacia, alginic acid and salts thereof,    cellulose derivatives, methylcellulose, hydroxyethyl cellulose,    hydroxypropyl cellulose, magnesium aluminum silicate, polyethylene    glycol, gums, polysaccharide acids, bentonites, hydroxypropyl    methylcellulose, gelatin, polyvinylpyrrolidone,    polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone,    povidone, polymethacrylates, hydroxypropylmethylcellulose,    hydroxypropylcellulose, starch, pregelatinized starch,    ethylcellulose, tragacanth, dextrin, microcrystalline cellulose,    sucrose, or glucose, and the like.-   (b) Disintegration agents such as starches, pregelatinized corn    starch, pregelatinized starch, celluloses, cross-linked    carboxymethylcellulose, sodium starch glycolate, crospovidone,    cross-linked polyvinylpyrrolidone, croscarmellose sodium, a calcium,    a sodium alginate complex, clays, alginates, gums, or sodium starch    glycolate, and any disintegration agents used in tablet    preparations.-   (c) Filling agents such as lactose, calcium carbonate, calcium    phosphate, dibasic calcium phosphate, calcium sulfate,    microcrystalline cellulose, cellulose powder, dextrose, dextrates,    dextran, starches, pregelatinized starch, sucrose, xylitol,    lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol,    and the like.-   (d) Surfactants such as sodium lauryl sulfate, sorbitan monooleate,    polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile    salts, glyceryl monostearate, Pluronic™ line (BASF), and the like.-   (e) Solubilizer such as citric acid, succinic acid, fumaric acid,    malic acid, tartaric acid, maleic acid, glutaric acid sodium    bicarbonate and sodium carbonate and the like.-   (f) Stabilizers such as any antioxidation agents, buffers, or acids,    and the like, can also be utilized.-   (g) Lubricants such as magnesium stearate, calcium hydroxide, talc,    sodium stearyl fumarate, hydrogenated vegetable oil, stearic acid,    glyceryl behapate, magnesium, calcium and sodium stearates, stearic    acid, talc, waxes, Stearowet, boric acid, sodium benzoate, sodium    acetate, sodium chloride, DL-leucine, polyethylene glycols, sodium    oleate, or sodium lauryl sulfate, and the like.-   (h) Wetting agents such as oleic acid, glyceryl monostearate,    sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate,    polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan    monolaurate, sodium oleate, or sodium lauryl sulfate, and the like.-   (i) Diluents such lactose, starch, mannitol, sorbitol, dextrose,    microcrystalline cellulose, dibasic calcium phosphate, sucrose-based    diluents, confectioner's sugar, monobasic calcium sulfate    monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate,    dextrates, inositol, hydrolyzed cereal solids, amylose, powdered    cellulose, calcium carbonate, glycine, or bentonite, and the like.-   (j) Anti-adherents or glidants such as talc, corn starch,    DL-leucine, sodium lauryl sulfate, and magnesium, calcium, or sodium    stearates, and the like.-   (k) Pharmaceutically compatible carrier comprises acacia, gelatin,    colloidal silicon dioxide, calcium glycerophosphate, calcium    lactate, maltodextrin, glycerine, magnesium silicate, sodium    caseinate, soy lecithin, sodium chloride, tricalcium phosphate,    dipotassium phosphate, sodium stearoyl lactylate, carrageenan,    monoglyceride, diglyceride, or pregelatinized starch, and the like.

Additionally, drug formulations are discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton, Pa. 1975. Another discussion of drug formulations can be foundin Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980.

The phrase “accessory system” refers to a device enabling fluid accessinto an access port.

The term “connector” refers to a device used for connecting tubes,catheters, reservoirs, pumps, access ports that are in fluidcommunication in a way that the fluid communication is given and thefluid communication is prevented from disconnection by mechanicalstrain.

The phrase “convection enhanced delivery” refers to delivery of asolvent inducing a bulk flow current into a target tissue or tumor thathas the potential to homogeneously distribute even large moleculesthrough long distances throughout the tissue or tumor. This is alsoknown as high pressure microperfusion.

The term “distal” refers to that part of the device that is upstream inthe flow direction when viewed from the tumor or tissue into which theinfusion catheter is implanted.

The phrase “expanding volume” refers to any flexible device or apparatusdownstream the pump additionally integrated into the tubing forsmoothing the peaks of the flow induced by the pump. The casing of theexpanding volume therefore has to be flexible enough to compensate flowpeaks/pressure peaks respectively. The lumen of the expanding volume isexpanding during the time the pump feeds the solvent and the lumen iscontracting during the interval the pump feeds no solvent, therefore,smoothing the peaks of the downstream flow of the device.

The expanding volume can be, for example, a balloon, a membrane, a softtube etc.

The phrase “fluid pharmaceutical agent” refers to a fluid containing apharmaceutical substance in a dispersed or dissolved form.

The phrase “interval therapy” refers to the administration of a fluidpharmaceutical agent at least once during a certain time period, forexample, within minutes, hours, days, or weeks, in alternation with atleast one other fluid pharmaceutical agent and/or physiological solvent.

The phrase “means for injection” refers to a device that can induce aflow or singular bolus of a solvent, and includes, for example, a pump,a syringe, a balloon, a piston, etc.

The phrase “needle screen” refers to a device for preventing an accessport needle with a certain form or diameter from penetration fromanother access port needle with a similar or different form or diameter.The needle screen can be of any appropriate material known in the art,such as, for example, a netting material of appropriate diameter, or afoil with perforation of a certain diameter or form, etc.

The phrase “one way valve” refers to a device, such as a valve, forexample, that allows fluid flow in substantially in only one direction.

The phrase “physiological solvent” refers to a fluid that isadministered into the subject and is used in conjunction with or withouta fluid pharmaceutical agent. A physiological solvent typically is of acomposition that is physiologically compatible with the subject, andtypically has a substantially similar pH and salt concentration as thetarget tissue or tumor. Illustratively, a physiological solvent is anaqueous solution of 0.9% sodium chloride at about a pH of about 6 toabout 7.

The phrase “portable pump” refers to a pump having a weight andconfiguration that allows easy transport by the subject whilemaintaining the fluid flow rate characteristics that can be used with anapparatus described herein. For an adult human, for example, the maximumweight of a portable pump ranges, for example, from about less thanabout 1 kg to about less than 0.05 kg, or is less than about 0.75 kg, orless than about 0.5 kg, or less than about 0.25 kg, or less than about0.1 kg, in an unfilled condition. Such portable pumps can be carriedclose to the body keeping the hands of the subject free, and can besecured to the body, for example, by a leather pouch fixed at the belt.Illustratively, a device such as a rolling stand, for example, is notneeded when the patient is moving, thus providing full mobility whiletreatment is ongoing. Furthermore, in one embodiment of the presentinvention, the pump is easily maintainable, but robust enough to provideconstant flows while the subject is moving in a manner appropriateduring treatment (for example, walking, sitting, and/or laying).Additionally, in another embodiment, the portable pump is configured(for example, secured buttons and programs) such that there issubstantially little or no danger of unintentional changes of the pumpfunctions during daily-life activity. For ease of treatment and patientuse, refilling of the solvent reservoir and reprogramming the pumpshould be simple and easy to understand without the need for anyadditional sophisticated devices, which is typical for an outpatientsetting.

The term “proximal” refers to that part of the device that is downstreamin the flow direction when viewed from the tumor or tissue into whichthe infusion catheter is implanted.

The term “septum” refers to a material covering the distal part of anaccess port enabling a needle to be inserted through it without loosingits seal around the needle or loosing its seal after the needle has beenwithdrawn. In one embodiment, the septum is pliable and capable ofmaintaining a seal after a needle has been inserted and withdrawn on oneor more occasions.

The term “solvent” refers to a solvent such as a physiological fluid ora fluid pharmaceutical agent that can be infused with the device of thepresent invention.

The term “ventricular shunt” refers to fluid communication betweenintraspinal liquid and a body cavity, such as, for example, a vein or anintraperitoneal space, or a second access port system in fluidcommunication with, for example, an external solvent reservoir.

The present invention is further illustrated by the following examples,which should not be construed as limiting in any way.

EXAMPLES Example 1

In this example, an isotropic 0.4% agarose gel model was used. (ChenZ-J, 2002). This gel was put into a transparent acrylic cube of 7 cm inlength for a total volume of approximately 340 mL. Evans blue dye with amolecular weight of 960.8 was infused under carefully controlledconditions on the bench for a period of 24 hours and photographs weretaken of the resultant infusion pattern. Images were taken at 0, 1, 3,6, 12 and 24 hours of infusion time. The syringe pump used forin-subject treatment, Graseby 3200, (Sims Graseby Ltd, Watford, Herts,UK) was compared with the radial piston pump Pegasus Vario (PegasusGmbH, Germany) using two different catheters. First a polyimide tubewith 0.02 mm inner diameter and 0.85 mm outer diameter was used for theinfiltration of the solvent. Secondly a ventricular catheter withmultiple side holes (4 rows of 8 holes, for a total of 32 holes, fromPromedics GmbH, Düsseldorf, Germany) was used for the infiltration.

Different flows were used. FIG. 4 b depicts the distribution at a flowrate of 0.48 μL/h with the radial piston pump under test “PegasusVario.” FIG. 4 b depicts the corresponding distribution of the “Graseby3200” syringe pump at the same flow rate of 0.48 mL/h.

Surprisingly the “Pegasus Vario” radial piston pump, which has not beenaccepted for convection enhanced delivery purpose so far, showeddistribution patterns over the time (FIG. 4 b) as good as the convectionenhanced delivery-approved syringe pump “Graseby 3200” did (FIG. 4 a).

The experiment was also done with an average flow rate of 240 μL/h inwhich the results were comparable.

Example 2

For an application system for the treatment of glioma, a portable radialpiston pump was used and included an infusing tube and the reservoir bagfrom LogoMed GmbH, Windhagen, Germany. The type of the portable pump was“Pegasus Vario” having a reservoir of polyurethane with a capacity of 50mL. The infusing tube had a length of 100 cm in which a flat sterilefilter (0.22 μm pore diameter) was integrated. An infusion needle, aGripper®-needle (22G), with lengths of 16, 19, 25 and 32 mm was usedfrom Smith Medical Deutschland GmbH, Kirchseeon, Germany). The accessport PORT-A-CATH, low profile, made of titan, as well as the accessport-catheter, were both purchased from Smiths Medical Deutschland,Kirchseeon, Germany. The access port catheter was made of silicon andimpregnated with material to absorb x-rays and was connected with oneinfusion catheter (tumor catheter) by a CSF-catheter connector made ofnylon from Promedics GmbH Düsseldorf, Germany.

As depicted in FIG. 1, the infusion catheter was surgically implantedwith its perfusion holes ending in the brain in the center of the tumor(glioma), and was affixed on the scull. The access port chamber wasconnected with the access port catheter and was implanted on thesubject's rib and the access port catheter was laid towards the open endof the infusion catheter, which was positioned in a manner cervically.The overlapping end of the access port catheter was shortened so that itwas loose enough to follow movements of the body without influencing theexact position of the infusion catheter when connected and was thencombined with the connector to the infusion catheter. All implanteddevices were filled with a physiological solution prior to implantation.

The reservoir, pump head, infusion tubing and access port needle werefilled with the solution that was infused, and the pump with thereservoir was positioned at an appropriate region of the body with, forexample, a belt around the waist. The access port needle was thenpricked through the skin the fatty tissue and the septum into thesubcutaneously placed access port and then infusion was started.

The flow during the time the pharmaceutical active substance AP 12009was administered varied between 200 μL/h and 500 μL/h for 4-7 days.

During the 7 days when no fluid pharmaceutical agent was administeredthe system was rinsed with 0.06 mL/h of isotonic sodium chloridesolution. These cycles were repeated 6-13 times leading to a total timeof the treatment of about half a year.

Example 3

This experiment was done to compare the flow characteristic of theconvection enhanced delivery approved syringe Pump “Graseby® 3200” withthe Portable Pump “Pegasus Vario.” The measurement was performed at“Institut für Mikro- and Informationstechnik derHahn-Schickard-Gesellschaft e. V.”, Wilhelm-Schickard-Strasse 10, 78052Villingen-Schwenningen, Germany.

The measurements were carried out at the “Liquid Flow” measuring site ofthis Institute.

To exclude external influences all measurements were carried out on avibration damped desk.

In a first step the calibration curve of the sensor used for thisexperiment was calibrated applying the hydrostatic principle by which aflow is induced by connecting two tanks of different levels with tubes.The sensor used was SP45, type 300×600 tp 45, channel 0.8 mm×0.4 mm,heating power 20 mW (20V).

The pumps were measured in combination with the devices that were usedin Example 1. Briefly, the pump with the reservoir was connected withthe infusing tube with a filter and an access port needle, access port,access port catheter, connector and infusion catheter. To beappropriately connectable with the test device, the infusion catheterwas shortened in length just behind the perfusion holes viewed from thetip. The fluid used for the test system was water.

The results of the flows measured in this experiment are depicted inFIGS. 2 a and 2 b for the syringe pump “Graseby® 3200” and in FIGS. 3 aand 3 b for the “Pegasus Vario.”

For all formulations herein, doses may be compounded as is known in theart.

The invention has been described in an illustrative manner, and it is tobe understood the terminology used is intended to be in the nature ofdescription rather than of limitation. All patents and other referencescited herein are incorporated herein by reference in their entirety.Many modifications, equivalents, and variations of the present inventionare possible in light of the above teachings, therefore, it is to beunderstood that within the scope of the appended claims, the inventionmay be practiced other than as specifically described.

1. An apparatus comprising: a. an extracorporeal solvent reservoircomprising a distal portion, a proximal port and a lumen extendingthere-through; b. an extracorporeal portable pump comprising a proximalport and a distal port and a lumen therethrough wherein theextracorporeal portable pump is in fluid communication with theextracorporeal solvent reservoir; c. an infusion catheter configured forinsertion into the tumor of the subject, the infusion cathetercomprising a length extending from a proximal end for introduction intothe tumor to a distal end with a lumen extending between the proximalend and the distal end wherein the infusion catheter is in fluidcommunication with the solvent reservoir and portable pump; d. anintracorporeal access port comprising an access port casing, two or moreaccess port chambers defined within the casing, each access port chamberhaving a proximal port, a distal port and a lumen extendingtherebetween, a pliable septum covering the distal port of each chamber,wherein the intracorporeal access port is located proximal from theextracorporeal portable pump and facilitates fluid communication between(i) the extracorporeal solvent reservoir and extracorporeal portablepump, and (ii) the infusion catheter; and e. means for convectionenhanced delivery of a solvent to a target tumor, wherein the solventdelivered by convection enhanced delivery has (i) a flow rate at thetarget tumor of more than 0.001 ml/h and less than 1 ml/h; (ii) a totalflow volume within one period of any oscillation of less than about 0.5μl; and (iii) an amplitude of oscillation between about 0.05 ml/h andabout 1 ml/h.
 2. The apparatus of claim 1, further comprising: a. atleast one access port catheter comprising a proximal port, a distalport, and a lumen extending therethrough, wherein the proximal port ofthe access port catheter is in fluid communication with (i) the infusioncatheter lumen and (ii) one of the distal ports of the access portchambers; b. at least one infusion tube configured for connection to oneof the distal ports of the access port chambers, the infusion tubecomprising a length extending from a proximal end for introduction intothe distal end of the access port chamber, to a distal port opposite theproximal end, and a lumen extending therethrough.
 3. The apparatus ofclaim 2, further comprising a filter system.
 4. The apparatus of claim3, wherein the filter system comprises one or more separate filters. 5.The apparatus of claim 4, wherein the filter system comprises a sequenceof two or more filters.
 6. The apparatus of claim 5, wherein the filtersystem comprises filters placed in a sequence, from upstream todownstream, of an air filter, a particle filter, and a sterile filter.7. The apparatus of claim 4, wherein each separate filter comprises adistal port, a proximal port, a lumen therethrough, and a membranedisposed within the lumen.
 8. The apparatus of claim 4, wherein the oneor more filters are a sterile filter for removing pathogens, abiological filter for removing biological material, a particle filterfor removing particulates, a chemical filter for removing chemicals, ora filter for removing gasses from the solvent.
 9. The apparatus of claim4, wherein the filter system comprises a filter having a pore size ofabout 0.45 μm or less.
 10. The apparatus of claim 4, wherein the filtersystem comprises a filter having a pore size of about 0.22 μm orgreater.
 11. The apparatus of claim 4, wherein the filter systemcomprises a filter having a pore size of about 0.45 μm or greater. 12.The apparatus of claim 2, further comprising two or more infusioncatheters, and a distributor disposed between the proximal port of theaccess port catheter and the distal ends of the two or more infusioncatheters.
 13. The apparatus of claim 12, wherein the distributorcomprises a plurality of proximal ports, equivalent to the number ofinfusion catheters, a distal port, and an interconnected lumen disposedthere between, wherein the distal port of the distributor is connectedto, and in fluid communication with, a proximal port of the access portcatheter, and wherein the proximal ports of the distributor areconnected to, and in fluid communication with, the distal ends of thetwo or more infusion catheters.
 14. The apparatus of claim 13, whereinthe equivalent internal diameters of the distributor's proximal portsare less than the internal diameter of the distributor's distal port.15. The apparatus of claim 13, wherein the internal diameters of theeach of the proximal ports of the distributor are different from eachother.
 16. The apparatus of claim 2, wherein the two or more access portchambers are configured to be penetrated by a needle one or more timeswithout loosing fluid containment integrity.
 17. The apparatus of claim16, wherein the infusion tube further comprises an access port-needle atthe proximal port of the infusion tube adopted for insertion into one ofthe distal ports of the access port chambers.
 18. The apparatus of claim2, wherein the access port further comprises a distal access portchamber disposed above a proximal access port chamber, wherein theseptum for the proximal access port chamber is integrated into thebottom of the distal access port chamber and separates the proximal anddistal access port chambers.
 19. The apparatus of claim 18, wherein theaccess port further comprises a needle screen located on the bottom ofthe distal access port chamber, adjacent to, and covering, the septum ofthe proximal access port chamber.
 20. The apparatus of claim 2, furthercomprising a ventricular shunt in fluid communication with the accessport system.
 21. The apparatus of claim 2, further comprising anexpanding volume having a lumen in fluid communication with a lumendownstream of the portable pump.
 22. The apparatus of claim 2, whereinat least one of the infusion catheter, the infusion tube, and the accessport catheter are made from polyvinylchloride material.
 23. Theapparatus of claim 2, wherein the lumen of the infusion catheter,infusion tube, and access port tube has an inner diameter of betweenabout 0.1 mm to about 5 mm.
 24. The apparatus of claim 1, wherein theinfusion catheter further comprises a plurality of perfusion holes. 25.The apparatus of claim 24, wherein the infusion catheter furthercomprises a marker wire to allow for monitoring the position of theinfusion catheter.
 26. The apparatus of claim 24, wherein the lumen ofthe infusion catheter comprises a plurality of separate lumens.
 27. Theapparatus of claim 24, wherein the infusion catheter further comprises afixation device attached thereto, for affixing the infusion catheter toa solid tissue or bone.